Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress
Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress
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DOI：
10.1073/pnas.0402531101
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发表时间：
2004-06-01
影响因子：
11.1
通讯作者：
Bazan, NG
中科院分区：
文献类型：
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作者：
Mukherjee, PK;Marcheselli, VL;Bazan, NG
二十二碳六烯酸（DHA）是视网膜色素上皮（RPE）和视网膜氧化损伤的脂质过氧化作用靶点。在所有细胞膜中，光感受器和突触膜的DHA含量最高。这种脂肪酸是RPE功能完整性所必需的;然而，目前尚不清楚DHA产生的特定介质是否有助于其生物学意义。我们使用人ARPE-19细胞并证明了10，17 S-二十二碳三烯[神经保护素D1（NPD 1）]的合成。这种合成通过钙离子载体A-23187、IL-1 β或提供DHA来增强。在这些条件下，内源性游离DHA的释放是时间依赖性的，随后是NPD 1的形成，这表明磷脂酶A（2）释放了介质的前体。添加NPD 1可有效抵消H2 O2/肿瘤坏死因子a氧化应激引发的凋亡性RPE DNA损伤。NPD 1还上调抗凋亡蛋白Bcl-2和Bcl-x（L）的表达，降低促凋亡蛋白Bax和Bad的表达。此外，NPD 1（50 nM）抑制氧化应激诱导的caspase-3活化。NPD 1还抑制IL-1 β刺激的转染入ARPE-19细胞的环氧合酶2启动子的表达。总的来说，NPD 1保护RPE细胞免受氧化应激诱导的凋亡，我们预测它将类似地保护神经元。因此，这种脂质介质也可能间接有助于感光细胞的存活。由于RPE和感光细胞在视网膜变性中死亡，我们的研究结果有助于理解视网膜细胞存活信号，并可能开发新的治疗策略。
Docosahexaenoic acid (DHA) is a lipid peroxidation target in oxidative injury to retinal pigment epithelium (RPE) and retina. Photoreceptor and synaptic membranes share the highest content of DHA of all cell membranes. This fatty acid is required for RPE functional integrity; however, it is not known whether specific mediators generated from DHA contribute to its biological significance. We used human ARPE-19 cells and demonstrated the synthesis of 10,17S-docosatriene [neuroprotectin D1 (NPD1)]. This synthesis was enhanced by the calcium ionophore A-23187, by IL-1beta, or by supplying DHA. Under these conditions, there is a time-dependent release of endogenous free DHA followed by NPD1 formation, suggesting that phospholipase A(2) releases the mediator's precursor. Added NPD1 potently counteracted H2O2/tumor necrosis factor a oxidative-stress-triggered apoptotic RPE DNA damage. NPD1 also up-regulated the antiapoptotic proteins Bcl-2 and Bcl-x(L) and decreased proapoptotic Bax and Bad expression. Moreover, NPD1 (50 nM) inhibited oxidative-stress-induced caspase-3 activation. NPD1 also inhibited IL-1beta-stimulated expression of cyclooxygenase 2 promoter transfected into ARPE-19 cells. Overall, NPD1 protected RPE cells from oxidative-stress-induced apoptosis, and we predict that it will similarly protect neurons. This lipid mediator therefore may indirectly contribute to photoreceptor cell survival as well. Because both RPE and photoreceptor cells die in retinal degenerations, our findings contribute to the understanding of retinal cell survival signaling and potentially to the development of new therapeutic strategies.